PROJECT SUMMARY HTLV-1 is the etiological agent of adult T-cell leukemia lymphoma (ATLL). ATLL cells are characterized by constitutive NFB activation, a key feature of other lymphomas, myeloma, and solid tumors. The Tax oncoprotein is the key viral determinant for NFB activation. Our previous studies showed that the classical and especially, the alternative NFB pathways were critical in conferring resistance to apoptosis. Our primary hypothesis is that Tax activation of NFB is critical for tumorigenesis, particularly the alternative (alt) NFB pathway. The current study will use innovative, physiological lymphoma models to define the role in tumorigenesis of each NFB pathway and identify the key regulators of the NFB pathway. Aim 1. Aim 1. To assess the role of alt NFB activity in Tax-mediated transformation A new humanized mouse model is used for HTLV-1 infection and lymphoma development. We will use viral variants expressing Tax mutants with defects in activating the alternative NFB pathway or both NFB pathways, in order to define their role in disease pathogenesis. A novel high-throughput viral integration assay is used to monitor clonality of infected cells in these experiments. Aim 2. To identify and characterize Tax interactive proteins that mediate alt NFB activation We will identify Tax interactive proteins that mediate alt NFB pathway activation. Proteins that interact with wild type but not mutant Tax will then be characterized using shRNAs to assess their effect on Tax induced cleavage of alt NFB precursor protein, p100, as well as effects on proliferation and apoptosis of HTLV-1 transformed cells in culture and immunodeficient mice. It is expected that the information these physiologically relevant mouse models will identify key target genes that may be inhibited in therapeutic trials of ATLL or other lymphomas.